Herpes simplex virus 1 (HSV-1) is a human pathogen that efficiently establishes lifelong infections that can manifest as a variety of disease states that vary depending on the host and the site of infection. These diseases include orolabial herpes, presenting with the recurrence of painful and psychologically distressing cold sores around the lips, and herpes keratitis, in which recurrence in the eye results in inevitable loss of vision, making HSV-1 the leading cause of infectious blindness in the developed world. Between 50-90% of adults in the U.S. are estimated to be infected with HSV-1, with incidence approaching 100% for the subpopulation over the age of 60. While the majority of hosts are asymptomatic, viral shedding occurs spontaneously, resulting in propagation of infection. Similar to HSV-1, HSV-2 also establishes a lifelong infection, with a greater prevalence for recurrence at the genital mucosa.
Following local replication at the site of primary infection with either virus, the virus enters into the nervous system via sensory nerve termini. Once in the nuclei of sensory ganglia neurons, the ≈153 kb HSV-1 double stranded linear DNA genome enters into a closed circular episomal form. The episome rapidly becomes associated with cellular histones that largely bear epigenetic modifications associated with transcriptional repression, resulting in the transcriptional inactivity of lytic genes that is the hallmark of latency. However, in defined regions of the genome, histones are associated with permissive histone modifications, which allow for accessibility to the DNA, and low levels of transcription. This transcription permits the accumulation of the only transcript abundantly expressed during latency, the latency-associated transcript (LAT), as well as a number of HSV-1 encoded microRNAs (miRNAs). Together, these transcripts are thought to play a role in the regulation of viral latency and reactivation. Spontaneously, and/or in response to a multitude of stressors, the HSV-1 episome undergoes reactivation, resulting in a lytic cascade of gene expression, replication of the viral genome, and subsequent egress of infectious virions.
Antivirals exist with broad activity against herpesvirus DNA replication, and these present the U.S. with an economic burden of over $500,000,000 annually. Importantly, these antivirals only limit the duration of reactivation events when used reactively, or limit the frequency of reactivation events when used proactively, while neither impacting latent infection nor allowing for a reduction/cure of the viral burden. HSV can develop resistance to commonly used antivirals such as acyclovir, and HSV is also not amenable to traditional vaccination schemes. Alternative chemotherapeutic treatments for latent infection are impeded by the absence of protein targets produced by the quiescent virus.
This disclosure seeks to alleviate these issues by providing distinct approaches to treat and/or cure latent viral infections, such as HSV-1 and HSV-2 infections, by significantly reducing or eliminating the latent viral load and thus reducing or eliminating recurrent disease. While these approaches are described using HSV-1 as a model pathogen in this application (owing to its simpler laboratory manipulation), nearly identical methods are adaptable to other viruses, such as HSV-2, other neurotropic herpes viruses (including Varicella zoster virus (VZV), the causative agent of shingles and post-herpetic neuralgia) and other viruses.